Efficacy of pazopanib monotherapy in patients who had been heavily pretreated for metastatic soft tissue sarcoma: A retrospective case series

Yoo et al. BMC Cancer (2015) 15:154
DOI 10.1186/s12885-015-1160-x

RESEARCH ARTICLE

Open Access

Efficacy of pazopanib monotherapy in patients
who had been heavily pretreated for metastatic
soft tissue sarcoma: a retrospective case series
Kwai Han Yoo1†, Hyo Song Kim2†, Su Jin Lee1, Se Hoon Park1, Sung Joo Kim3, Soo Hee Kim4, Yoon La Choi5,
Kyoo-Ho Shin6, Yong Jin Cho6, Jeeyun Lee1* and Sun Young Rha2*

Abstract
Background: We retrospectively reviewed outcomes of treatment with pazopanib, an oral multi-tyrosine kinase
angiogenesis inhibitor, in patients with advanced soft tissue sarcoma, a rare and heterogeneous tumor group with
limited treatment options.
Methods: Between 2009 and 2013, 43 patients with metastatic soft tissue sarcoma received pazopanib as salvage
chemotherapy after one or more cytotoxic regimens. Response rate, progression-free survival, and overall survival
were analyzed according to histological subtype, Eastern Cooperative Oncology Group performance status, and
metastatic site.
Results: Common histological subtypes included leiomyosarcoma (n = 9), angiosarcoma (n = 6), malignant fibrous
histiocytoma/undifferentiated pleomorphic sarcoma (MFH/UPS, n = 5), malignant peripheral nerve sheath tumor
(MPNST, n = 5), and synovial sarcoma (n = 4). Nineteen patients (44.2%) received more than two chemotherapy
regimens before pazopanib. At the time of analysis, 208 treatment cycles of pazopanib had been administered
(median, 4.8 cycles per patient), and no treatment-related mortality occurred. The disease control rate was 61.0%
(95% confidence interval [CI], 46.1–75.9%), and the overall response rate was 17.1% (partial response, n = 7; complete
response, n = 0). Partial response was achieved in two patients with synovial sarcoma, two with MFH/UPS, one with
MPNST, one with leiomyosarcoma, and one with angiosarcoma. The median lengths of progression-free survival
and overall survival were 5.0 months (95% CI, 3.6–6.4 months) and 8.2 months (95% CI, 5.8–10.6 months), respectively.
Progression-free survival was shorter in the patients with liposarcoma and rhabdomyosarcoma (1.3 and 0.9 months,

respectively) than in those with leiomyosarcoma, MPNST, MFH/UPS, and synovial sarcoma (5.6, 6.5, 7.1, and 7.7 months,
respectively).
Conclusions: Pazopanib demonstrated acceptable antitumor activity in the Asian patients who had been heavily
pretreated for sarcoma, with seemingly more favorable results in the patients with leiomyosarcoma, MPNST, MFH/UPS,
and synovial sarcoma than in those with liposarcoma and rhabdomyosarcoma.
Keywords: Histological type, Pazopanib, Soft tissue sarcoma

* Correspondence: ;
†
Equal contributors
1
Division of Hematology and Oncology, Department of Medicine, Samsung
Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro,
Gangnam-gu, Seoul 135-710, Republic of Korea
2
Division of Medical Oncology, Department of Internal Medicine, Yonsei
Cancer Center, Yonsei University College of Medicine, 50 Yonsei-ro,
Seodaemun-Gu, Seoul 120-752, Republic of Korea
Full list of author information is available at the end of the article
© 2015 Yoo et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License ( which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain
Dedication waiver ( applies to the data made available in this article,
unless otherwise stated.


Yoo et al. BMC Cancer (2015) 15:154

Background
Soft tissue sarcomas (STS) are a rare and heterogeneous

group of tumors that originate from mesenchymal cells
and account for 1% of all adult malignancies [1,2]. The
primary treatments of STS are surgery and radiotherapy.
However, approximately 40% of patients experience
tumor recurrence, and survival rate is poor, with a median overall survival (OS) of less than 12 months [3].
STS is comprised of more than 50 different histological
subtypes [4] that differ greatly in terms of treatment response and prognosis [2]. Despite this heterogeneity, patients with advanced non-gastrointestinal stromal tumor
STS are generally treated in the same manner. However,
chemosensitivity varies according to tumor subtype, and
survival is also influenced by tumor grade, patient age,
and performance status [5]. For instance, angiosarcoma
is responsive to paclitaxel [6-9], and uterine leiomyosarcoma generally shows a good response to high-dose
gemcitabine combined with docetaxel [10].Anthracyclines and ifosfamide, either alone or in combination,
are the gold standard treatments of advanced STS [3,11].
However, after failure of conventional first-line cytotoxic
chemotherapy, available treatment options are severely
limited because of a high risk-to-benefit ratio in terms
of patient tolerability and survival. Hence, the availability of less toxic agents that can improve chances of
progression-free survival (PFS) or OS is crucial. In light
of this, a recent pivotal phase III trial in refractory sarcoma patients (the PALETTE trial) demonstrated a significantly prolonged median PFS associated with pazopanib
treatment.
Pazopanib is a synthetic indazolylpyrimidine that functions as a multitargeted tyrosine kinase inhibitor (TKI)
with a high affinity for vascular endothelial growth factor
receptors and a low affinity for platelet-derived growth
factor receptors, fibroblast growth factor receptors, and
c-Kit [12]. Based on the results of the PALETTE trial,
pazopanib is currently recommended as the gold standard treatment for patients with metastatic nonadipocytic STS after failure of standard chemotherapy.
However, only strictly selected patients with specific
histological subtypes such as non-adiopocytic sarcoma
were included in the clinical trial, and clinical use of

pazopanib in unselected patients has not yet been fully
documented. Furthermore, most patients enrolled in the
PALETTE study were of Caucasian ancestry and only 57
of the 247 patients in the pazopanib group (23.2%) were
from Asian ancestry (by personal communication with
GSK). A recent phase II pazopanib trial demonstrated
that Asian patients with nasopharyngeal carcinoma tolerated the treatment well, with a similar toxicity profiles
[13]. However, the efficacy and tolerability of pazopanib
in Asian patients with sarcoma are scarcely reported.
Hence, the efficacy and tolerability of pazopanib in Asian

Page 2 of 7

patients should be evaluated. Therefore, we retrospectively investigated the anti-tumor efficacy of pazopanib in
heavily pretreated STS patients from two major Korean
cancer centers and conducted a subgroup analysis according to histological subtype.

Methods
Patients and treatment

We retrospectively reviewed the medical records of
patients with advanced STS who were treated with
pazopanib between May 2009 and November 2013 at
Samsung Medical Center and Yonsei University College
of Medicine, South Korea. The inclusion criteria were
as follows: (1) pathologically confirmed STS and (2)
availability of complete clinical information, including
patient demographic characteristics, primary tumor
site, tumor stage, and treatment record. The following
clinicopathological variables were collected: age, sex, histological type, extent of metastasis, Eastern Cooperative

Oncology Group (ECOG) performance status, and
treatment history. The study was reviewed and approved
by the Institutional Review Board of Samsung Medical
Center and Yonsei University College of Medicine.

Treatment

Pazopanib was administered orally at a dose of 800 mg
once daily. The dose was reduced to 600, 400, or 200 mg
for the management of adverse events at the discretion
of the physician. Treatment was repeated every 4 weeks
and continued until disease progression, unacceptable
toxicity, or patient refusal. Evaluation of tumor response
was performed every 2 months based on computed
tomographic or magnetic resonance imaging findings.
Responses were assessed according to the Response
Evaluation Criteria in Solid Tumors, version 1.1 [14].
Statistical analysis

Standard descriptive and analytical methods were used
to describe the patient population and their baseline
characteristics. OS was defined as the time from the
initiation of pazopanib treatment to the date of death
or last follow-up. PFS was defined as the time from initiation of the pazopanib treatment to the date of documented disease progression or death from any cause.
Kaplan-Meier estimates were used to analyze time-toevent variables, and 95% confidence intervals (CIs)
were computed for time-to-event medians. Survival
comparisons were performed using univariate log-rank
tests. The Cox proportional hazards model was used
for multivariate analyses. Two-tailed P < 0.05 was considered statistically significant. Statistical analysis was
performed using the SPSS version 18 software (SPSS

Inc., Chicago, IL, USA).


Yoo et al. BMC Cancer (2015) 15:154

Results

Page 3 of 7

Table 1 Patient demographics and clinical characteristics

Patient characteristics

Between May 2009 and November 2013, 43 patients with
relapsed or refractory STS were treated with pazopanib as
at least a second-line chemotherapy. The patients’ baseline
characteristics at the start of the pazopanib treatment are
summarized in Table 1. The median age of the patients
was 54 years (range, 19–74 years), and 60.5% of the patients were male. Most patients (86.0%) had a good ECOG
performance status (i.e., 0 or 1). The distribution of histological subtypes was as follows: leiomyosarcoma (n = 9),
angiosarcoma (n = 6), malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma (MFH/UPS, n = 5),
malignant peripheral nerve sheath tumor (MPNST, n = 5),
and synovial sarcoma (n = 4). FNCLCC (French Fédération
Nationale des Centres de Lutte Contre le Cancer) grades
were available for 22 patients (51.2%), of whom 13 (59.1%)
had grade 3 sarcoma. The primary tumor site was the
trunk or retroperitoneum in 34 patients (79.1%) and the
extremities in 9 patients (20.9%). The most common
metastatic sites were the lung (n = 32, 74.4%), bone (n =
17, 39.5%), and liver (n = 12, 27.9%).

All of the patients had previously received at least one
cytotoxic chemotherapy regimen before pazopanib treatment, and most of the patients had been heavily pretreated
with at least two previous cytotoxic regimens. Fifteen
patients (34.9%) had received two prior regimens, and 19
patients (44.2%) had received three or more prior regimens. In the study cohort, the following patients had received prior regimens: 69.8% (n = 30), doxorubicin-based
chemotherapy; 90.7% (n = 39), ifosfamide-based chemotherapy; 74.4% (n = 32), taxane-based chemotherapy; and
65.1% (n = 28), gemcitabine-based chemotherapy.
Pazopanib therapy was administered in 208 treatment cycles, with a median of 4.8 cycles per patient (range, 1–17
cycles). At the time of analysis, 6 patients were still receiving pazopanib treatment, and the remaining 37 patients
had stopped treatment because of progression (n = 30), patient refusal (n = 1), toxicity (n = 1), or other reasons (n = 5).
The most common non-hematological toxicities were
diarrhea (grade 3 or 4, n = 2), hand-foot syndrome
(grade ≥ 2, n = 6), and anorexia (grade 3 or 4, n = 2). The
grade 3 or 4 hematological toxicities were neutropenia
(n = 1) and thrombocytopenia (n = 1). No treatmentrelated mortality or neutropenic fever was associated with
pazopanib treatment. Most non-hematological toxicities
were reversible with appropriate medical management (e.g.,
loperamide for diarrhea) and dose reduction. The pazopanib dose was reduced in 48.8% of the patients (n = 21).
Tumor responses

Of the 43 patients, 41 were evaluable for tumor response.
Figure 1 shows the maximum response after pazopanib
treatment. None of the patients achieved a complete

n

%

43

100

Median

54

—

Range

19-74

—

Male

26

60.5

Total
Age

Gender

ECOG PS

Histology

FNCLCC grade

Primary site

Organ involvement

Number of prior chemotherapy
regimens chemotherapies

Agents used in prior regimen(s)

Cycles of pazopanib treatment

Female

17

39.5

0

7

16.3

1

30

69.8

2

6

14.0

Leiomyosarcoma

9

20.9

Angiosarcoma

6

14.0

MFH/UPS

5

11.6

MPNST

5

11.6

Fibroblastic tumor

4

9.3

Synovial sarcoma

4

9.3

Rhabdomyosarcoma 3

7.0

Liposarcoma

2

4.7

Tumor of uncertain
differentiation

3

7.0

Desmoplastic small

cell tumor

1

2.3

PEComa

1

2.3

1

3

7.0

2

6

14.0

3

13

30.2

unknown

21

48.8

Trunk or
retroperitoneum

34

79.1

Extremity

9

20.9

Lung

32

74.4

Liver

12

27.9

Bone

17

39.5

1

9

20.9

2

15

34.9

≥3

19

44.2

Doxorubicin

30

69.8

Ifosfamide

39

90.7

Taxane

32

74.4

Gemcitabine

28

65.1

Dacarbazine

6

14.0

Median

4.8

—

Range

1-17

—

ECOG = Eastern Cooperative Oncology Group, PS = performance status, MFH/
UPS = malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma,
MPNST = malignant peripheral nerve sheath tumor, PEComa = perivascular
epithelioid cell tumor, FNCLCC = French Fédération Nationale des Centres de
Lutte Contre le Cancer.


Yoo et al. BMC Cancer (2015) 15:154

Page 4 of 7

Figure 1 Maximum response to pazopanib treatment.

response, but seven patients achieved partial responses,
yielding a 17.1% (95% CI, 5.6–28.6%) overall response
rate. Responses were observed in the patients with synovial sarcoma (n = 2, 50%), MFH/UPS (n = 2, 40%),
MPNST (n = 1, 20%), leiomyosarcoma (n = 1, 11%), and
angiosarcoma (n = 1, 17%). Of the seven patients with
partial responses, three maintained treatment response
for more than 10 cycles at the time of this writing.
Eighteen patients (43.9%) achieved stable disease, at a
disease control rate of 61.0% (95% CI, 46.1–75.9%).
Thus, objective tumor response or stable disease for

more than 12 weeks was attained in 51.2% of the patients
(n = 22; 95% CI, 43.6–58.8%), and the median response
duration was 251 days (range, 30–469 days).

with liposarcoma (n = 2) had poorer survival after pazopanib treatment than those with other types of sarcoma
(Additional file 1: Figure S2A). Of note, the patients with
RMS progressed to pazopanib rapidly, but were all alive
at the time of this writing. Age (>50 years vs ≤50 years,
P = 0.079), number of prior chemotherapy regimens (≥2
vs 0–1, P = 0.162), primary site (truck/retroperitoneum
vs extremity, P > 0.05), and existence of liver and lung
metastases (presence vs absence, P = 0.756) were not significantly correlated with PFS at univariate level. However, performance status (ECOG 2 vs. 0 or 1, P = 0.034)
and prior response to doxorubicin (stale response or
progression vs partial response, P = 0.05) at the time of
pazopanib treatment were significant adverse factors of
pazopanib treatment in terms of PFS.

Survival outcomes

At a median follow-up of 12.0 months (95% CI, 5.7–
18.3 months), the median PFS was 5.0 months (95% CI,
3.6–6.4 months), and the median OS was 8.2 months
(95% CI, 5.8–10.6 months). We analyzed PFS and OS in
patients with different histological subtypes (Table 2).
Patients with liposarcoma or rhabdomyosarcoma had
significantly poorer survival when compared with patients with non-liposarcoma or non-RMS cases (P < .001,
Additional file 1: Figure S1A). Accordingly, the patients

Discussion
We demonstrated that pazopanib is a feasible treatment

option with acceptable antitumor activity in patients
who had been heavily pretreated for metastatic STS.
Considering that a few patients in the previous clinical
trials were of Asian ethnicity [15-17], our study also
shows that pazopanib is well tolerated in Asian STS
patients.


Yoo et al. BMC Cancer (2015) 15:154

Page 5 of 7

Table 2 Survival of patients with various histologic subtypes
Histology

n

%

PFS [months, (95% CI)]

OS [months, (95% CI)]

Leiomyosarcoma

9

20.9

5.6 (2.7-8.5)

9.9 (5.3-14.4)

Angiosarcoma

6

14.0

3.2 (2.1-4.2)

8.0 (3.7-12.4)

MFH/UPS

5

11.6

7.1 (0.3-13.8)

7.5 (1.1-13.9)

MPNST

5

11.6

6.5 (0.7-12.3)

8.9 (3.5-14.3)

Fibroblastic tumor

4

9.3

5.7 (0.7-10.8)

6.4 (1.6-11.2)

Synovial sarcoma

4

9.3

7.7 (3.5-11.9)

9.4 (4.4-14.5)

Rhabdomyosarcoma

3

7.0

0.9 (0.5-1.3)

2.5 (0.7-4.4)

Liposarcoma

2

4.7

1.3 (0.7-1.9)

1.5 (1.1-1.8)

Tumor of uncertain differentiation

3

7.0

1.4 (0.5-2.3)

4.1 (−0.4-8.5)

Desmoplastic small cell tumor

1

2.3

10.3 (N/A)

43.4 (N/A)

PEComa

1

2.3

3.8 (N/A)

4.1 (N/A)

Total

43

100

5.0 (3.6-6.4)

8.2 (5.8-10.6)

PFS = progression-free survival, CI = confidence interval, OS = overall survival, MFH/UPS = malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma,
MPNST = malignant peripheral nerve sheath tumor, PEComa = perivascular epithelioid cell tumor; N/A, not available.

Beyond standard systemic treatment with doxorubicin
and ifosfamide, newer agents such as gemcitabine, trabectedin, and pazopanib have been assessed for subsequent treatment of STS. In a phase III trial, pazopanib
treatment significantly improved PFS compared with
placebo, with a median prolongation of 3 months [16].

These results led to the approval of pazopanib for STS,
making it the first anti-angiogenic drug approved for
STS. In terms of efficacy, our study shows similar outcomes (PFS, 5.0 months and OS, 8.2 months) as those of
the PALETTE trial. However, our observation of shorter
OS compared with that in the PALETTE trial might be
because most of our patients had been heavily pretreated
with at least two prior chemotherapy regimens. Regarding
toxicity profile, despite the retrospective nature of our
study, we used the same dosage and dose modification
protocol as those used in the PALETTE trial. Similar frequency of dose reduction (48% in our cohort vs 39% in the
PALLETE trial) and treatment duration (median, 19 weeks
vs 16.4 weeks) were observed.Given the diverse histological subtypes of STS with different biological and clinical behaviors, an exploratory subgroup analysis according
to histological subtype was performed in previous trials
[15,16]. In the EORTC 63043 study, 142 patients were recruited into four different strata as follows: adipocytic
STS, leiomyosarcoma, synovial sarcoma, and other STS
types. Among the strata, the adipocytic sarcoma stratum
was closed due to poor PFS rate at 12 weeks. Based on this
phase II trial, adipocytic STS was excluded from the
PALETTE trial. In a recent subgroup analysis of longterm responders to pazopanib [17], patients with leiomyosarcomas and synovial sarcomas, vascular tumors,
alveolar soft part sarcoma, solitary fibrous tumors, and
desmoplastic small round cell tumors were the main
long-term responders and survivors. In line with these

results, we also observed better anti-tumor activity of
pazopanib in patients with non-adipocytic sarcoma
such as leiomyosarcoma, MPNST, MFH/UPS, or synovial
sarcoma but less activity in patients with adipocytic sarcoma or rhabdomyosarcoma.
With regard to treatment response to angiogenesis inhibitors such as pazopanib among patients with adipocytic
sarcoma, several trials have reported varying results from
subgroup analyses [16,18,19]. Similar to the PALETTE

trial, a phase II trial demonstrated that patients with liposarcoma were poor responders to sorafenib [18]. By contrast, patients with liposarcoma showed a promising
treatment response to sunitinib in a single-institution
study, with 3.9 months of PFS and 18.6 months of OS[19].
Currently, the underlying biological mechanism of poor
response to pazopanib in adiopocytic sarcoma has not
been defined, but it may depend on the heterogeneity of
adipocytic sarcoma subtypes (i.e., dedifferentiated, myxoid,
round cell, and pleomorphic). In our previous work, we
showed a distinct prognosis and the clinical features of
dedifferentiated liposarcoma among other adipocytic
sarcomas [20]. However, as all but two liposarcoma patients included in this analysis had myxoid liposarcoma, we
cannot draw definitive conclusions regarding treatment response to pazopanib according to different subtypes.
In terms of pediatric sarcomas, clinical activity with
pazopanib was demonstrated for desmoplastic small
round cell tumors and alveolar rhabdomyosarcoma in a
phase I study [21]. In our case series, poor responders
were patients with embryonal and spindle cell rhabdomyosarcoma who had failed to respond to four previous
cytotoxic regimens. Because these patients already had
refractory sarcoma at the time of pazopanib therapy, it is
difficult to define the anti-tumor activity of pazopanib in
this subset. However, these patients failed to respond to


Yoo et al. BMC Cancer (2015) 15:154

pazopanib within 2 months of therapy initiation, which
suggests that pazopanib is not an optimal treatment option
for this subtype. Nevertheless, because of our small sample
size, further observations are required regarding the effect
of pazopanib in adult-onset pediatric type sarcoma.

Some limitations of this study include its retrospective
nature and small sample size, especially for the histological subgroup analyses. However, to date, no study reports the efficacy of pazopanib specifically in an Asian
population. Furthermore, unlike well-controlled clinical
trials [15,16], our patient cohort was mostly composed
of individuals with poor performance status who had
been heavily pretreated.

Conclusion
In summary, we demonstrated that pazopanib is a feasible
option for the patients who had been heavily pretreated
for metastatic sarcoma, with a small subset of patients
achieving long-term responses. To gain insight into the
subgroup of patients who could benefit most from pazopanib, an expansion of the patient pool through a large
multicenter cohort study is needed.
Additional file
Additional file 1: Figure S1. Survival according to histological subtype.
A) Progression-free survival (PFS) and B) overall survival (OS).
Abbreviations
STS: Soft tissue sarcoma; OS: Overall survival; PFS: Progression-free survival;
TKI: Tyrosine kinase inhibitor; ECOG: Eastern Cooperative Oncology Group;
CI: Confidence interval; MFH/UPS: Malignant fibrous histiocytoma/
undifferentiated pleomorphic sarcoma; MPNST: Malignant peripheral nerve
sheath tumor; FNCLCC: French Fédération Nationale des Centres de Lutte
Contre le Cancer.
Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
SJK, KS, and YJC performed the surgical procedures and participated in the
review of the patients’ data. SHK and YLC participated in the pathological
review of the patients’ specimens. KHY, HSK, JL and SJL participated in the

design of the study and performed the statistical analysis. JL, HSK, KHY and
SYR conceived the study, participated in its design and coordination, and
drafted the manuscript. All of the authors read and approved the final
manuscript.
Author details
Division of Hematology and Oncology, Department of Medicine, Samsung
Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro,
Gangnam-gu, Seoul 135-710, Republic of Korea. 2Division of Medical
Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei
University College of Medicine, 50 Yonsei-ro,
Seodaemun-Gu, Seoul 120-752, Republic of Korea. 3Department of Surgery,
Samsung Medical Center, Sungkyunkwan University School of Medicine,
Seoul, Republic of Korea. 4Department of Pathology, Yonsei Cancer Center,
Yonsei University College of Medicine, Seoul, Republic of Korea. 5Department
of Pathology, Samsung Medical Center, Sungkyunkwan University School of
Medicine, Seoul, Republic of Korea. 6Department of Orthopedic Surgery,
Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic
of Korea.
1

Page 6 of 7

Received: 16 October 2014 Accepted: 4 March 2015

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